To elucidate the neurobiology of MDD, positron emission tomographic (PET) measures of serotonin~A (5HT1A) receptor binding and glucose metabolism will be compared between depressed and control subjects and between the pre-and post-treatment conditions of major depressive disorder (MDD). Previous studies assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor density in brain tissue acquired post mortem from small samples of MDD subjects, or examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration suggested that SHT1A receptor function is abnormal in MDD and that AD therapies induce changes in SHT1A receptor function that are relevant to treatment efficacy. However, there has been no direct demonstration of a central SHT1A receptor abnormality or an effect of AD treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for PET, [carbonyl 11C]-WAY- 100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. PET images of [carbonyl-11C]-WAY-100635 and 18F-fluorodeoxyglucose (FDG) uptake will be acquired in the same scan session in depressed and healthy controls to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Cortisol secretion prior to imaging is also assessed to determine whether the down-regulation of hippocampal 5HT1A receptors seen in rats exposed to repeated stress or exogenous glucocorticoids also results from hypercortisolism associated with MDD. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the selective serotonin reuptake inhibitor, citalopram. This project takes the PI's career development in the new direction of neuroreceptor imaging. The training and research plans build upon his previous experience in conducting PET studies of blood flow and metabolism by adding capabilities for determining whether brain regions where physiological abnormalities are found in depression are also characterized by abnormal serotonin receptor pharmacology. The PI will acquire skills for characterizing the in vivo binding characteristics of a novel PET radioligand in humans and baboons, for implementing various tracer kinetic models for the derivation of receptor BP, and for comparing receptor image data between depressed and healthy samples. Training is also received in the application of multivariate statistical approaches and neural network modelling techniques for assessing interrelationships between regional 5HT1A receptor BP, metabolism, and cortisol in multiple interconnected structures.